The musculoskeletal system is critical for movement and the protection of organs. In addition to abrupt
injuries, daily physical demands inflict minor
injuries, necessitating a coordinated process of repair referred to as the
acute-phase response (APR). Dysfunctional APRs caused by severe
injuries or underlying
chronic diseases are implicated in pathologic musculoskeletal repair, resulting in decreased mobility and
chronic pain. The molecular mechanisms behind these phenomena are not well understood, hindering the development of clinical solutions. Recent studies indicate that, in addition to regulating intravascular clotting, the coagulation and fibrinolytic systems are also entrenched in tissue repair. Although
plasmin and
fibrin are considered antithetical to one another in the context of hemostasis, in a proper APR, they
complement one another within a coordinated spatiotemporal framework. Once a
wound is contained by
fibrin, activation of
plasmin promotes the removal of
fibrin and stimulates angiogenesis, tissue remodeling, and tissue regeneration. Insufficient
fibrin deposition or excessive
plasmin-mediated fibrinolysis in early
convalescence prevents injury containment, causing
bleeding. Alternatively, excess
fibrin deposition and/or inefficient
plasmin activity later in
convalescence impairs musculoskeletal repair, resulting in tissue
fibrosis and
osteoporosis, while inappropriate
fibrin or
plasmin activity in a synovial joint can cause
arthritis. Together, these pathologic conditions lead to
chronic pain, poor mobility, and diminished quality of life. In this review, we discuss both
fibrin-dependent and -independent roles of
plasminogen activation in the musculoskeletal APR, how dysregulation of these mechanisms promote musculoskeletal degeneration, and the possibility of therapeutically manipulating
plasmin or
fibrin to treat
musculoskeletal disease.